The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes. The serotonin 5-HT2 class is further subdivided into at least three subtypes, designated 5-HT2a, 5-HT2b, and 5-HT2c. The 5-HT2c receptor has been isolated and characterized (Julius, et al., U.S. Pat. No. 4,985,352), and transgenic mice lacking the 5-HT2c receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius, et al., U.S. Pat. No. 5,698,766). Compounds selective for the 5-HT2c receptor would provide useful therapies for the treatment of seizure and eating disorders without the side effects associated with current therapies.
Hartog (Hartog, et al., U.S. Pat. No. 5,424,313) generically describes a number of benzofurylpiperazines which are taught to be useful as psychotropics, central analgetics, and thrombolytics. The use of benzofuryl-piperazines as selective 5-HT2c agonists has heretofore not been appreciated. The present invention provides compounds selective for the 5-HT2c receptor.
The present invention provides compounds of Formula I: 
where R is methyl or ethyl, or pharmaceutically acceptable acid addition salts thereof.
This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I.
The present invention provides a method for increasing activation of the 5-HT2C receptor in mammals comprising administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
The present invention also provides a method for treating obesity in mammals comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of Formula I.
A further embodiment of this invention is a method for increasing activation of the 5-HT2C receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are obesity, obsessive compulsive disorder, and depression. Any of these methods employ a compound of Formula I.
This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of obesity. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of obesity containing a compound of Formula I. Furthermore, this invention includes a method for the treatment of obesity which comprises administering an effective amount of a compound of Formula I.
The compounds of Formula I are generally referred to as 1-(4-trifluoromethylbenzofur-7-yl)-3(S) -methylpiperazine when R is methyl, and 1-(4-trifluoromethylbenzofur-7-yl)-3(S)-ethylpiperazine when R is ethyl. Since this compound is an amine, it is basic in nature and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. It is preferable to convert the free amine to a pharmaceutically acceptable acid addition salt for ease of handling and administration. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex2-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid and fumaric acid.
The compounds of Formula I may be prepared by chiral chromatography of the racemic or enantiomerically enriched free amines, or fractional crystallization of salts prepared from racemic or enantiomerically enriched free amines and a chiral acid. Alternatively, the free amines may be reacted with a chiral auxiliary and the enantiomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amines. Furthermore, separation of enantiomers may be performed at any convenient point in the synthesis of the compound of the invention. Preferably, the compounds of the invention are prepared beginning with chiral starting materials.
The present invention also provides a method for increasing activation of the 5-HT2C receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I. The preferred mammal is human.
Compounds of Formula I may be prepared as described in the following scheme, beginning with 4-trifluorometh-yl-7-(substituted)-benzofuran and 2(S)-methyl- or ethylpiperazine. 
The 4-trifluoromethylbenzofur-7-yl bromide, iodide, or triflate is reacted with 2(S)-methyl- or ethylpiperazine in the presence of an appropriate catalyst and base. The coupling is catalyzed with an appropriate metal catalyst, such as nickel or palladium. Palladium catalysts are preferred and are either commercially available or may be generated in situ by combining trisdibenzylideneacetone dipalladium or palladium chloride with a phosphine ligand such as racemic 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, tri-o-tolylphosphine, or bis(diphenylphosphino)ferrocene. The ratio of palladium to phosphine ligand is typically between 1:1 and 1:5. Typically 0.01 to 0.1 equivalents of catalyst are used relative to starting benzofuran. Useful bases include sodium tert-butoxide, lithium tert-butoxide, and potassium tert-butoxide. Typically 1-5 equivalents of base are used relative to starting benzofuran.
The benzofuran, piperazine, catalyst, and base are combined in a suitable solvent. Suitable solvents include toluene, benzene, dioxane, and tetrahydrofuran. The mixture is stirred at 20-200xc2x0 C. under an inert atmosphere, typically nitrogen or argon, until the reaction is complete. Additional portions of any reagent may be added during the course of the reaction as necessary or desired. Typically, 1-1.2 equivalents of the piperazine are reacted with the benzofuran.
Alternatively, the compounds of Formula I may be prepared as described in the following scheme. 
The piperazine ring may be constructed onto the benzofuryl moiety by coupling 4-trifluoromethyl-7-bromo-benzofuran with benzophenone imine under the coupling conditions previously described. The resulting adduct is treated with aqueous acid to provide the corresponding amine. This aminobenzofuran is coupled with an appropriately nitrogen-protected (S)-alanine (when R=methyl) or (S)-2-aminobutyric acid (when R=ethyl) under standard peptide coupling conditions. The resulting amide is reduced with a hydride reducing agent such as lithium aluminum hydride, and the corresponding amine deprotected to provide a diamine. The diamine is treated with an appropriate reagent, for example bromoacetyl bromide, to prepare the corresponding lactam. Reduction of this lactam under standard hydride reducing conditions, for example by treatment with borane or lithium aluminum hydride, provide the desired compound.
The requisite benzofuran is either commercially available or may be prepared from an appropriately substituted phenol by methods well known in the art as illustrated in the following scheme. 
A solution of an appropriately substituted phenol in a suitable solvent, typically dimethylformamide, is treated with a base, to generate the corresponding phenoxide. Bases useful for this reaction include hydride sources, such as sodium or potassium hydride, or carbonates, such as sodium or potassium carbonate. The phenoxide solution is then reacted with a chloro- or bromoacetaldehyde protected as a cyclic or dialkyl acetal. Bromoacetaldehyde diethyl acetal is particularly useful for this reaction. The phenoxyacetaldehyde acetal prepared by this procedure is reacted with a source of acid in a suitable solvent to provide the desired benzofuran. Suitable solvents include aromatic solvents such as toluene, xylene, benzene, and halobenzenes such as chlorobenzene. Suitable acids include concentrated sulfuric acid, polyphosphoric acid, and acidic resins such as Amberlyst 15(trademark).
Alternatively, the phenoxide solution is treated with an allyl bromide or allyl chloride to provide, after standard isolation and purification procedures, the corresponding allyl ether. This purified ether is heated at a temperature sufficient to effect an ortho-Claisen rearrangement to provide the corresponding o-allylphenol. It is critical that the allyl ether employed in this rearrangement is substantially free of residual dimethyl-formamide. The o-allylphenol is then treated with an excess of ozone in an appropriate solvent, dichloromethane and methanol are useful solvents for this step. The reaction mixture is then purged of ozone and the ozonide is treated under reducing conditions, typically by treatment with triphenylphosphine or dimethylsulfide, to provide the corresponding phenylacetaldehyde. The skilled artisan will appreciate that the orientation of the aldehyde with the respect to the phenolic hydroxyl group gives rise to the formation of a cyclic hemiacetal. This hemiacetal exists in some equilibrium mixture with the free hydroxyaldehyde. A solution of this equilibrium mixture in a suitable solvent, such as toluene, is treated with a catalytic amount of an appropriate acid, such as sulfuric acid, to provide the desired benzofuran.
The requisite benzofurans may also be prepared from an appropriately substituted phenol as illustrated in the following scheme. 
A mixture of an appropriate phenol and hexamethylene-tetramine are treated with an appropriate acid, such as trifluoroacetic acid, to provide upon aqueous workup the corresponding o-formylphenol. This o-formylphenol is then treated with (bromomethyl)triphenylphosphonium bromide followed by an appropriate base such as potassium tert-butoxide to provide the desired benzofuran.
R
The requisite 2(S)-methylpiperazine is commercially available (Aldrich Chemical Company, Milwaukee, Wis. U.S.A.) Alternatively, both 2(S)-methylpiperazine and 2(S)-ethylpiperazine may be prepared by methods well known in the art (Org. Prep. Proced. Int., 22, 761 (1990)). One such approach is illustrated in the following scheme that illustrates the preparation of 2(S)-methylpiperazine. The skilled artisan will appreciate that 2(S)-ethylpiperazine can also be prepared by the route illustrated in the scheme. 
An appropriately N-protected (S)-alanine or (S)-2-aminobutyric acid is coupled with an N-benzylated carboxy-protected amino acid under standard peptide coupling conditions to provide the corresponding dipeptide. This dipeptide is N-deprotected and heated to provide the corresponding dilactam. This dilactam is reduced under standard hydride reducing conditions, for example with lithium aluminum hydride, to provide the corresponding N-benzylated piperazine. The N-benzyl group is removed by either catalytic hydrogenation or by treatment with 1-chloroethyl chloroformate to provide the corresponding piperazine. The benzyl group may be removed either prior or subsequent to coupling with an appropriate benzofuran depending upon the specific coupling orientation desired as described supra.